The present invention is directed to secondary and tertiary amino methylated 2-pyridinones, to methods of their preparation and to their use for inhibiting pili formation in bacteria.
The core structure of 2-pyridinones, or more commonly referred to as 2-pyridones, is present in a wide range of compounds with diverse biological application areas. Besides showing e.g., antibacterial,1 antifungal2 and anti-tumor activity,3,4 members of these heterocycles also act as inhibitors of a Aβ-peptide aggregation thought to play an important role in Alzheimers' disease.5 An enantioselective ketene imine cycloaddition reaction to synthesize ring fused substituted 2-pyridones has previously been reported.6,7 Starting from commercially available nitrites and carboxylic acids, this synthetic pathway rendered a first generation of 2-pyridones that were designed to target periplasmic escort proteins, chaperones, in uropathogenic Escherichia coli. Chaperones are essential for the assembly of adhesive protein organelles known as pili or fimbriae present on the surface of the bacteria, in absence of these organelles the bacteria become non-infectious.8 Thus, compounds interfering with pili/fimbriae formation, pilicides, would represent a novel class of antibacterial agents directed against bacterial virulence considered a promising avenue in drug development.9 
Encouraging affinity predictions of substituted 2-pyridones binding to the chaperones PapD and FimC have previously been confirmed in vitro by direct binding assays using both surface plasmon resonance techniques and NMR spectroscopy, where the corresponding acid of 4a was found to be a potent binder.10 Recently, efficient improvements of the original synthetic procedure were reported.11 This alternative microwave assisted method allows simple and fast preparation of highly substituted 2-pyridones in good yields and with limited racemization. Still, position six is available for further substitution and thus provides an opportunity to introduce hydrophilic functionalities targeting increased bioavailability and enhanced chaperone affinity in the pilicide project. Incorporation of a cyano group would provide a precursor to a number of interesting derivatives such as carboxylic acids,12 tetrazoles,13 and amidines.14 Nitriles can also be converted into primary amines and inspired by former observations in drug development this appeared to be an attractive target. For example in the case of Ampicillin and Amoxycillin, the introduction of an amine substituent led to a broad spectrum antibiotic also affecting Gram-negatives.15 In addition, introducing amine substituents in the 2-pyridone framework would result in highly substituted rigid amino acids, which could serve as versatile scaffolds and peptide mimetics.16 
Aromatic cyanodehalogenation and subsequent reduction of the cyano functionality was considered a well cited and straightforward pathway towards amino methylated 2-pyridones.17,18 As a complement to the primary amines, and to expand the chemical diversity of these structures, tertiary amines were also desired. A few scattered examples where 2-pyridones react with imines in a Mannich reaction in the corresponding position have previously been described19,20 and recently, microwave mediated Mannich reactions performed with electron-rich aromatic substrates have also been published.21,22 Nevertheless, applications on more complex structures such as functionalized 2-pyridones with a challenging substitution pattern have previously not been reported.